Diabetes Mellitus (DM) is a metabolic disease of multiple causes, and is a syndrome of a series of metabolism disorder of protein, fat, water, electrolytes and the like caused by absolute or relative lack of insulin secretion in the human body or reduced sensitivity of target cells to insulin. Acute complications of diabetes include diabetic ketoacidosis, diabetic hyperosmolar coma, a variety of acute infection and lactic acidosis and so on. In addition, hypoglycemia existed in the treatment of diabetes is also one of the most common acute complications. Chronic complications of diabetes include diabetic eye disease, diabetic nephropathy, diabetic neuropathy, diabetic heart and brain limbs macrovascular disease and diabetic foot and skin lesions etc.
Type II diabetes is a type of metabolic syndrome caused by uncontrolled blood glucose levels in vivo. Type II diabetes is characterized by high blood glucose, insulin resistance and lack of insulin secretion, and is usually associated with dyslipidemia, hypertension and obesity. Type II diabetes is a global epidemic, and all over the world 6% of the population are currently suffering from type II diabetes, which has become the world's third chronic non-communicable diseases threatening human health. Type II diabetes patients can produce insulin in the human body, but the quantity is relative insufficient, or the obtained insulin can not function effectively due to reduced tissue sensitivity or insulin resistance, so glucose accumulates in blood and glucose level is increased. Since this type of diabetes patients can secrete insulin, insulin therapy is generally not needed, and blood glucose can be controlled only by diet adjustment or oral hypoglycemic agents.
In 2000, there were about 171 million diabetics in the world. It is expected that if there is no effective treatment, in 2030, the number of diabetics will reach 360 million, of which more than 90% are type II diabetes. In China, diabetes treatment costs up to 173.4 billion RMB per year, diabetes-induced direct medical expenses have accounted for 13% of China's total medical expenditure. It is expected that the number of diabetic patients in the United States will reach 50 million in 2028 with an annual growth rate of 5%. While in China the number of diabetes patients up to 92.5 million now is expected to reach 100 million in 2028 with an annual growth rate of 4%. As a complex disease, type II diabetes patients have strong heterogeneity, and Easterners have a higher susceptibility to type II diabetes than Westerners, and demand for individualized treatment is high.
Current drugs for treating type II diabetes mainly include insulin, sulfonylureas, metformin, thiazolidinediones, PPARα/γ double agonists, DPP IV inhibitors and GLP-1 analogs. Although the existing drugs can control blood glucose levels and reduce the occurrence of complications, but most of them have more serious side effects, such as gastrointestinal toxicity, weight gain, edema, hypoglycemia and the like, and they can not fundamentally control and cure type II diabetes. Since traditional diabetes treatment drugs have limited effect and poor tolerance as well as obvious side effects, from the perspective of human health and economic interests, it has important research significance to research and develop safe and highly efficient diabetes treatment drugs.
DPP IV inhibitors can significantly reduce blood glucose levels in the body, increase glucose tolerance, promote insulin secretion, reduce glucagon level, delay insulin resistance and increase response level of insulin when blood glucose increases in patients with type II diabetes. Compared with existing oral diabetes drugs, DPP IV inhibitors have following characteristics: (1) DPP IV inhibitors do not require injections, and continuously reduce glycosylated hemoglobin level by oral administration; (2) DPP IV inhibitors have good tolerance after long-term use; (3) DPP IV inhibitors can enhance insulin secretion and improve the release of glucagon; (4) DPP IV inhibitors improve insulin sensitivity and increase pancreatic β cell function; (5) lower incidence of hypoglycemia, and it will not cause weight gain, nausea and vomiting and gastrointestinal dysfunction; (6) DPP IV inhibitors have synergistic effects when they are used with other type II diabetes drugs.
(R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl)-4-carbonyl-3,4-dihydroth iophene[3,2-d] pyrimidine-6-carboxylic acid (Formula I) is a novel DPP IV inhibitor with strong activity of reducing blood glucose in vivo. However, the overall performance of the existing various crystalline forms of (R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl)-4-carbonyl-3,4-dihydrothiop hene[3,2-d] pyrimidine-6-carboxylic acid is still unsatisfactory.
Therefore, there is an urgent need in the art for the development of a new crystal form of (R)-methyl-2-(3-aminopiperidin-1-yl)-3-(2-cyanobenzyl)-4-carbonyl-3,4-dihydrothiop hene[3,2-d] pyrimidine-6-carboxylic acid with high efficiency, low toxicity and long-lasting effect so as to obtain a pharmaceutically active ingredient with better performance.